title: Novel compound 1,3-bis (3,5-dichlorophenyl) urea inhibits lung cancer progression.
abstract: The successful clinical management of lung cancer is limited by frequent loss-of-function mutations in p53 which cooperates with chronic oxidant-stress induced adaptations in mercapturic acid pathway (MAP) which in turn regulates critical intracellular signaling cascades that determine therapeutic refractoriness. Hence, we investigated the anti-cancer effects and mechanisms of action of a novel compound called 1,3-bis(3,5-dichlorophenyl) urea (COH-SR4) in lung cancer. Treatment with COH-SR4 effectively inhibited the survival and clonogenic potential along with inducing apoptosis in lung cancer cells. COH-SR4 treatment caused the inhibition of GST activity and G0/G1 cell cycle arrest and inhibited the expression of cell cycle regulatory proteins CDK2, CDK4, cyclin A, cyclin B1, cyclin E1, and p27. The COH-SR4 activated AMPK pathway and knock-down of AMPK partially reversed the cytotoxic effects of COH-SR4 in lung cancer. COH-SR4 treatment lead to regression of established xenografts of H358 lung cancer cells without any overt toxicity. The histopathology of resected tumor sections revealed an increase in pAMPK, a decrease in the nuclear proliferative marker Ki67 and angiogenesis marker CD31. Western-blot analyses of resected tumor lysates revealed a decrease in pAkt and anti-apoptotic protein Bcl2 along with an increase in pAMPK, pro-apoptotic protein Bax and cleaved PARP levels. Importantly, COH-SR4 lead to decrease in the mesenchymal marker vimentin and increase in the normal epithelial marker E-cadherin. The results from our in-vitro and in-vivo studies reveal that COH-SR4 represents a novel candidate with strong mechanistic relevance to target aggressive and drug-resistant lung tumors.
authors.affiliation: Departments of Diabetes & Metabolic Diseases Research, and Medical Oncology, Beckman Research Institute, City of Hope, Comprehensive Cancer Center, Duarte, CA 91010, USA. Electronic address: ssinghal@coh.org.
authors.forename: Sharad S
authors.initials: SS
authors.lastname: Singhal
authors.forename: James
authors.initials: J
authors.lastname: Figarola
authors.forename: Jyotsana
authors.initials: J
authors.lastname: Singhal
authors.forename: Lokesh
authors.initials: L
authors.lastname: Nagaprashantha
authors.forename: David
authors.initials: D
authors.lastname: Berz
authors.forename: Samuel
authors.initials: S
authors.lastname: Rahbar
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: C577482:1,3-bis(3,5-dichlorophenyl)urea; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds
keywords: 1,3-bis (3,5-dichlorophenyl) urea “City of Hope compound”; ACC; AMP-activated protein kinase; AMPK; COH-SR4; GST; Lung Cancer; SR4; TSC2; Tumor xenografts; acetyl Co-A carboxylase; glutathione S-transferase; tuberous sclerosis complex 2 protein